The overall aim of this application is to better understand the mechanism(s) that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various diverse mechanisms that drive the progression of prediabetes to diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. However, it is apparent that TCF7L2 regulates multiple genes regulating metabolic processes, all of which may be important in the pathogenesis of diabetes. Beta-cell function has been quantified by the Disposition Index (DI) which expresses insulin secretion as a function of insulin action. However, the relationship between these 2 parameters has been assumed to be uniform across various states of glucose tolerance, and indeed different states of beta-cell reserve. Direct measurement of the secretory response in response to an acute decrease in insulin action validate or improve DI as a characterization of beta-cell function and the effect of diabetes-associated variation in TCF7L2 on this measurement. Moreover, incretin hormones (regulated by TCF7L2 have been suggested to be part of the compensatory response to acute decreases in insulin action. Hepatic insulin action is impaired early in the pathogenesis of prediabetes and is characterized by impaired suppression of gluconeogenesis. The contribution of diabetes-associated variation in TCF7L2 to these processes is unknown. Finally, insulin secretion and insulin action decline in parallel across the spectrum of prediabetes. The mechanism(s) underlying this observation are unknown. One potential explanation, supported by animal experiments, is that decreased interdigestive insulin pulsatility leads to decreased hepatic insulin action. The processes regulating the amplitude and frequency of insulin secretion are complex and have been shown to be abnormal in many states associated with increased predisposition to diabetes. A direct effect of diabetes-associated variation in TCF7L2 on insulin pulsatility and amplitude of secretion is unknown. The experimental design will also allow direct correlation of interdigestive insulin secretion with hepatic insulin action in humans. The proposed experiments will directly address how TCF7L2 alters glucose homeostasis and provide insights into the pathogenesis of prediabetes and progression to diabetes. PUBLIC HEALTH RELEVANCE: Genome-wide association studies have identified multiple common genetic variants that predisposed to type 2 diabetes. Of these genetic variation in TCF7L2 has the strongest effect on diabetes risk. However, its direct effects on glucose metabolism and on progression to diabetes are poorly understood. Diabetes-associated variation in this locus provides an opportunity to improve our understanding of the processes driving the conversion of prediabetes to diabetes, refine clinical measurements of beta-cell function and improve our ability to target prevention strategies to predisposed individuals.